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新药创制是复杂的智力活动,涉及科学研究、技术创造、产品开发和医疗效果等多维科技活动。每个药物都有自身的研发轨迹,而构建化学结构是最重要的环节,因为它涵盖了药效、药代、安全性和生物药剂学等性质。本栏目以药物化学视角,对有代表性的药物的成功构建,加以剖析和解读。芬戈莫德是以真菌的次级代谢产物为先导物研发免疫调节剂的成功实例,于2010年上市,治疗免疫性疾病多发性硬化病。冬虫夏草是由于昆虫真菌感染所生成,具有增强免疫的功效,从中发现了天然活性物质。比对ISP-1与鞘氨醇结构的相似性,推测并证实ISP-1的作用靶标是鞘氨醇-1-磷酸(S1P)受体。在受体结构未知的情况下,用药物化学方法和构效分析成功地指导了优化过程,去除ISP-1中不必要的基团和手性中心是结构优化的策略。以电子等排和药效团原理指导后继药物的研发,赋予了结构新颖性和选择性作用。
The creation of new drugs is a complex intellectual activity involving multi-dimensional scientific and technological activities such as scientific research, technological creation, product development and medical effects. Each drug has its own development trajectory, and the construction of the chemical structure is the most important part, because it covers the properties such as efficacy, drug substitution, safety and biopharmaceutical. This column from the perspective of medicinal chemistry, representative of the successful construction of drugs, to be analyzed and interpreted. Fingolimod is a successful example of the development of immunomodulatory agents based on the secondary metabolites of fungi and was launched in 2010 to treat multiple sclerosis of immunological diseases. Cordyceps sinensis is due to fungal infections generated by insects, with enhanced immune function, from which the discovery of natural active substances. Comparing the similarity between ISP-1 and sphingosine structure, we speculate that ISP-1 is the target of sphingosine-1-phosphate (S1P) receptor. In the absence of receptor structure, the optimization process is successfully guided by chemical chemistry and structure-activity analysis. Removing unwanted groups and chiral centers in ISP-1 is a structural optimization strategy. The principle of electronic isoforms and pharmacophores to guide the development of follow-up drugs, given the structural novelty and selective role.